4. Surface-functionalized nanoparticle adjuvants for pulmonary immune modulation. Project Leader: Catherine Fromen (CBE) Respiratory diseases impact millions of people worldwide and novel advances are needed to improve prophylactic and treatment options. Inhalable vaccines have demonstrated notable efficacy, providing organ-specific responses and universal protection across alternative mucosa for improved barrier protection. However, development of efficient, cost-effective immune- modulatory therapies for inhalation remains elusive, owing to a lack of mucosal-specific adjuvants capable of delivering of precision molecular cues that yield highly regulated immune responses. To address this need, we will develop nanoparticle (NP)-based adjuvants specifically for inhalable delivery and identify the physiochemical features that lead to controlled lung immune profiles. Inspired by molecular interactions, we will inform the molecular design of NP adjuvants to provide precise signaling cues that direct specific T helper 1 (TH1), TH2, and TH17 immune responses in the lung, creating precision NPs that enable optimized delivery of novel pathogen associated molecular pattern (PAMP) ligands. Building on historical success of alum as a TH2 adjuvant, we will leverage the inherent low density and regularly ordered structure of metal organic framework (MOF) NPs to generate a novel class of porous aluminum-containing MOF adjuvants and evaluate their structure-functional adjuvant responses in the lung. In parallel, we will evaluate the role of specific physiochemical properties of these and polymeric-based adjuvant NPs to elucidate the role of net surface charge, pendant chemical species, NP degradation rate, and PAMP ligand valency (including highly purified bacterial peptidoglycan signaling molecules proposed by Grimes during Phase I) in driving specific adjuvant responses. The overall scientific outcomes of this project will be 1) generation of a new library of adjuvants with precise molecular designs 2) evaluation of our adjuvant systems for both lung-specific prophylactic vaccination and immune modulating therapies, and 3) establishment of a working set of design rules in regards to physiochemical NP properties for pulmonary therapeutics. The proposed studies will broadly improve fundamental understanding of adjuvant NP interactions and inform molecular-level design rules for pulmonary applications.